{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T16:48:05Z","timestamp":1758818885230,"version":"3.41.2"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec><jats:title>Aim<\/jats:title><jats:p>The dysregulation of hepatic lipid metabolism is closely associated with dyslipidemia. Previous research suggested that Hepatic <jats:italic>Morc4<\/jats:italic> may play a role in regulating lipid metabolism. This research aims to elucidate the function of MORC4 in hepatic lipid metabolism, thereby improving the understanding of the molecular mechanisms underlying lipid metabolism disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Data regarding circulating lipid traits and hepatic <jats:italic>Morc4<\/jats:italic> expression in BXD mice were obtained from GeneNetwork. An Expression-Based Phenome-wide Association Study (ePheWAS), correlation analysis, and gene enrichment analysis were conducted to explore the relationship between <jats:italic>Morc4<\/jats:italic> expression and hepatic lipid metabolism. <jats:italic>in vitro<\/jats:italic>, the levels of total cholesterol (TC) and triglycerides (TG), lipid accumulation, and the expression of lipid metabolism-related genes were assessed subsequent to <jats:italic>MORC4<\/jats:italic> knockdown\/overexpression in hepatocytes. <jats:italic>in vivo<\/jats:italic>, the impact of <jats:italic>Morc4<\/jats:italic> knockout on lipid metabolism-related traits in mice was examined using the IMPC database.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Hepatic <jats:italic>Morc4<\/jats:italic> level was found to be negatively correlated with plasma free fatty acids and triglycerides in BXD mice. Further analysis indicated that genes associated with <jats:italic>Morc4<\/jats:italic> were enriched in the cholesterol metabolic pathway. In hepatocytes, <jats:italic>MORC4<\/jats:italic> knockdown significantly elevated total TC\/TG levels, as well as enhanced lipid accumulation. Whereas <jats:italic>MORC4<\/jats:italic> overexpression restored total TC\/TG levels, along with lipid accumulation in knockdown cell lines. Furthermore, <jats:italic>MORC4<\/jats:italic> knockdown led to an increased expression of genes associated with cholesterol synthesis (<jats:italic>HMGCR<\/jats:italic>), varying levels of genes implicated in the uptake of fatty acids and cholesterol (<jats:italic>PCSK9, PLTP, CD36<\/jats:italic>), and a decrease in the levels of genes involved in triglyceride hydrolysis (<jats:italic>APOC2, APOA4, LIPG, LIPA<\/jats:italic>). <jats:italic>MORC4<\/jats:italic> overexpression reversed the observed alterations in the expression levels of these genes. According on the IMPC database, <jats:italic>Morc4<\/jats:italic> knockout in mice resulted in increased fat mass, fat\/body weight ratio, and elevated cholesterol level and ratio.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study identifies <jats:italic>MORC4<\/jats:italic> as a crucial regulator of hepatic lipid metabolism and underscores its potential as a therapeutic target for disorders related to lipid.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcvm.2025.1570729","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T13:55:28Z","timestamp":1750254928000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Morc4 is a novel functional gene associated with lipid metabolism in BXD recombinant inbred 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